Nanoparticle microbicides for delivery of combination antiretroviral drugs

用于递送组合抗逆转录病毒药物的纳米颗粒杀微生物剂

• 批准号: 8676646
• 负责人: Kim A. Woodrow
• 金额: $ 44.45万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-14 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8676646
• 关键词: AIDS prevention; Accounting; Adsorption; Animal Model; Anti-Retroviral Agents; Antiviral Agents; Architecture; Behavior; Biodistribution; Biological Availability; Biopsy; CCR5 gene; Cells; Charge; Chemicals; Chemistry; Clinical; Clinical Trials; Colposcopy; Cytology; Data; Detergents; Diffuse; Diffusion; Drug Carriers; Drug Combinations; Drug Delivery Systems; Drug Formulations; Drug Kinetics; Drug or chemical Tissue Distribution; Drug resistance; Drug usage; Encapsulated; Engineering; Epidemic; Epithelial; Epithelium; Exhibits; Female; Gel; Genital system; Geometry; HIV; HIV Infections; HIV-1; Highly Active Antiretroviral Therapy; Human; Hydrophobicity; In Vitro; Individual; Infection; Laboratories; Libraries; Local Microbicides; Macaca; Macaca nemestrina; Measures; Methods; Modeling; Mucous Membrane; Mucous body substance; Mus; Nevirapine; Organ Culture Techniques; Outcome; Particulate; Penetration; Pharmaceutical Preparations; Physiological; Prevention; Property; Prophylactic treatment; Research; Resistance; Ritonavir; Route; Safety; Saquinavir; Sexual Transmission; Sexually Transmitted Diseases; Solubility; Surface; Suspension substance; Suspensions; Techniques; Tenofovir; Time; Tissues; Topical application; Toxic effect; Vaccines; Vagina; Viral; Virus; Woman; aqueous; base; chemical stability; clinically relevant; controlled release; cytotoxicity; design; drug testing; efficacy testing; efficacy trial; empowered; flexibility; genital secretion; in vivo; inhibitor/antagonist; microbicide; nanoparticle; nanoparticulate; next generation; novel; polyanion; preclinical safety; prevent; protective efficacy; rectal; residence; response; safety study; screening; simian human immunodeficiency virus; success; transmission process; vaginal transmission

PROJECT SUMMARY/ABSTRACT Sexual transmission through the genital tract or rectal mucosa is the most common route for acquiring new HIV infections and accounted for ~70% of the 2.7 million people worldwide who became newly infected in 2007. A cure or effective vaccine that would contain the global spread of this epidemic is not expected in the near term, and new HIV infections continue to outpace advances made in treatment with antiretroviral drugs. There is consequently an urgent need to develop agents that can be applied topically to mucosal surfaces to prevent the sexual transmission of HIV. However, several large-scale clinical trials testing the efficacy of agents that disrupt the integrity of the viral envelope (detergents) or prevent adsorption or fusion of the virus with its target cells (polyanions) have failed to protect against HIV infection. The success of highly active antiretroviral therapy (HAART) provides a paradigm for developing the next generation of microbicides, raising the possibility that a combination of potent and broadly active inhibitors that exhibit multiple and complementary mechanisms of action may be vastly superior to the delivery of single compounds. To fully realize the potential of these potent antiretroviral (ARV) drugs, the challenges of formulating and delivering compounds with markedly different chemical stability and aqueous solubility in a topical combination product must be overcome. This research plan is designed to evaluate nanoparticle-based vaginal drug delivery systems for HIV prevention. The experimental focus is to achieve protection against vaginal transmission of HIV-1 by topical delivery of a combination of antiretroviral drugs using mucus- and tissue-diffusing nanoparticle microbicides. This research would be the first to control the temporal and spatial co-delivery of a combination of antiretroviral agents that have different mechanisms of action against HIV-1 (Aim 1). If successful, our studies would be the first to determine the size range and penetration depth accessible for nanoparticulate drug delivery systems in the vaginal mucosa (Aim 2). Our proposed research will also provide valuable data on the transport, biodistribution, and pharmacokinetics of encapsulated and released antiretroviral agents that are administered topically to the vaginal mucosa using nanoparticle microbicides (Aim 3). Finally, we will conduct preclinical safety and anti-HIV efficacy studies to rapidly advance our nanoparticle-based microbicides to human safety and efficacy trials (Aim 4). The outcomes from our proposed research may highly impact the field of microbicide research for HIV and other sexually-transmitted infections.

项目总结/文摘